PROJECT ABSTRACT The proposed project is designed to evaluate the effectiveness of cefixime (400mg, twice a day, for 10 days) compared to benzathine penicillin G (2.4 million units, intramuscularly) in patients with and without HIV infection. Syphilis rates have been increasing both in the US and internationally. Incidence is higher among men-who-have-sex-with-men and more importantly in individuals with HIV infection. Currently, penicillin is used to treat syphilis in patients with and without HIV infection. Doxycycline, tetracycline and ceftriaxone are alternative treatments for non-pregnant patients who are allergic to penicillin. Existing treatment alternatives are based on clinical experience, a limited number of small clinical trials, and case series, but each poses clinical challenges. New, safe and efficacious antibiotic treatment options are needed. In this proposal, we will build upon our successful pilot study to conduct a randomized, multisite, open-label, non- inferiority clinical trial to evaluate the effectiveness of cefixime (400mg, twice a day, for 10 days) compared to benzathine penicillin G (2.4 million units, intramuscularly) in patients with and without HIV infection. We will enroll 400 participants with early syphilis infection from 9 clinical sites in the U.S. and Peru. We will follow the participants to monitor clinical progress and serological response (RPR titer) every 3 months for 9 months. Our hypothesis is that cefixime will be non-inferior to penicillin in treating syphilis, shown as a 4-fold decrease in RPR titer from enrollment to 6-months after treatment administration. These are the two specific aims of our proposal. AIM 1: Evaluate the effectiveness of cefixime in the treatment of early syphilis when compared to benzathine penicillin G. AIM 2: Determine the predictors of treatment failure among participants. The 5 year project has 4 phases. Phase I will last 9 months and will involve the development of study instruments, staff training on recruitment, enrollment, and data collection. Phase II will last 36 months and will involve recruitment and enrollment of patients. Phase III which will last 45 months, but will start simultaneously as stage II, and will include the patient follow-up period. Phase IV will last 6 months and in that time, the data will be analyzed and disseminated.